Chronic Exposure of Mutant DISC1 Mice to Lead Produces Sex-Dependent Abnormalities Consistent With Schizophrenia and Related Mental Disorders: A Gene-Environment Interaction Study

Abstract

The glutamatergic hypothesis of schizophrenia suggests that hypoactivity of the N-methyl-D-aspartate receptor (NMDAR) is an important factor in the pathophysiology of schizophrenia and related mental disorders. The environmental neurotoxicant, lead (Pb(2+)), is a potent and selective antagonist of the NMDAR. Recent human studies have suggested an association between prenatal Pb(2+) exposure and the increased likelihood of schizophrenia later in life, possibly via interacting with genetic risk factors. In order to test this hypothesis, we examined the neurobehavioral consequences of interaction between Pb(2+) exposure and mutant disrupted in schizophrenia 1 (mDISC1), a risk factor for major psychiatric disorders. Mutant DISC1 and control mice born by the same dams were raised and maintained on a regular diet or a diet containing moderate levels of Pb(2+). Chronic, lifelong exposure of mDISC1 mice to Pb(2+) was not associated with gross developmental abnormalities but produced sex-dependent hyperactivity, exaggerated responses to the NMDAR antagonist, MK-801, mildly impaired prepulse inhibition of the acoustic startle, and enlarged lateral ventricles. Together, these findings support the hypothesis that environmental toxins could contribute to the pathogenesis of mental disease in susceptible individuals.

Cell Type-Specific Effects of Mutant DISC1: A Proteomics Study

“…In order to express mutant DISC1 in neurons or astrocytes, we mated either single hemizygous transgenic CaMKII-tTA (for neurons) or GFAP-tTA mice (for astrocytes, line 110) with single homozygous transgenic TRE-mutant DISC1 mice (line 1001) as described previously [5,10]. All mice were on the C57BL6/J background.…”

Utility and validity of DISC1 mouse models in biological psychiatry

“…First, these models highlighted several relevant cell types that are aberrantly regulated, including astrocytes (Abazyan et al, 2014), oligodendrocytes (Katsel et al, 2011), and CA1 pyramidal neurons (Booth et al, 2014), in addition to widely studied output and interneurons in the prefrontal cortex. Thus, roles for neuron-glia interaction in the pathology of mental illness may be tested in these models.…”

Dominant negative DISC1 mutant mice display specific social behaviour deficits and aberration in BDNF and cannabinoid receptor expression

“…Mouse models expressing mutant DISC1 are a useful tool to analyse gene -environment interaction in the generation of schizophrenia-like endophenotypes (Abazyan et al 2010(Abazyan et al , 2013Nagai et al 2011;Haque et al 2012;Lipina et al 2013;Niwa et al time spent in the centre of the arena during the open fi eld test, 6.76 Ϯ 3.9 in DN-DISC1 mice and 7.76 Ϯ 2.36 in control mice (% of time spent in centre Ϯ STD, P -value ϭ 0.5898). In the novel object recognition test, DN-DISC1 mice displayed similar preference towards the novel object both after 3-or 24-h retention ( Figure 1B), as observed by the ratio between time spent in proximity to the novel object and the total time spent in proximity either to the familiar or novel object.…”